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However, current diagnostic approaches, often limited to\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      mutation testing or genomic scars, fail to capture the full spectrum of HRD. Tissue-based testing is further hampered by tumour heterogeneity and biopsy limitations in patients with metastatic bone disease. This study aimed to develop a noninvasive, multimodal ctDNA-based strategy for comprehensive HRD profiling in advanced PCa.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed plasma-derived ctDNA from 106 patients with metastatic PCa. The approach integrated targeted sequencing of homologous recombination repair (HRR) genes, low-pass whole genome sequencing for genomic instability scores (GIS), whole-exome sequencing for mutational signature analysis, and cfDNA fragmentomics, including chromatin accessibility profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>BRCA2<\/jats:italic>\n                      was the most frequently altered HRR gene, frequently co-occurring with\n                      <jats:italic>PTEN<\/jats:italic>\n                      loss. High GIS was associated with\n                      <jats:italic>BRCA2<\/jats:italic>\n                      \/\n                      <jats:italic>RB1<\/jats:italic>\n                      loss, increased somatic copy number alterations, and poor overall survival. HRD tumours were enriched for mutational signatures SBS3 and ID6, displayed increased dinucleosome-length fragments, and showed reduced accessibility at zinc finger transcription factor binding sites. A fragmentomics-based classifier identified HRD-positive cases with high accuracy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings support the use of multimodal ctDNA profiling as a non-invasive approach to identify HRD in prostate cancer. The integration of mutation, genomic instability, and fragmentomic features provides a broader functional view of HRD and may enhance patient stratification for targeted therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41416-025-03301-0","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T18:40:37Z","timestamp":1767984037000},"page":"949-960","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional footprints of homologous recombination deficiency in prostate cancer revealed by ctDNA fragmentation and transcription factor accessibility"],"prefix":"10.1038","volume":"134","author":[{"given":"Georgios","family":"Vlachos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Moser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Lazzeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias J.","family":"Moser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Glawitch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil Thomas","family":"Bauernhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Eberhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Beichler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanieh","family":"Sadeghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Blatterer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00fchberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Monsberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2918-1370","authenticated-orcid":false,"given":"Angelika","family":"Terbuch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5803-4014","authenticated-orcid":false,"given":"Karl","family":"Kashofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen B.","family":"Geigl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9124-4876","authenticated-orcid":false,"given":"Thomas","family":"Bauernhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8815-7859","authenticated-orcid":false,"given":"Ellen","family":"Heitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"3301_CR1","first-page":"17","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A. 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